The Ras and Rho proteins function as critical transducers in the T-cell antigen receptor (TCR)-linked signaling cascade. These GTPases are activated by a family of guanine nucleotide exchange factors (GEFs) that includes Vav, a member of the Dbl family of GEFs. Earlier studies have shown that Vav cooperates with the Ras signaling cascade in activated T cells, and that the function of endogenous Vav may be quite different from that observed when the protein is over-expressed in mammalian cells. The following specific aims will be pursued: (1) to analyze the GEF activity of Vav, and to determine the impact of protein tyrosine phosphorylation on this activity, (2) to study the function of Vav in signaling pathways leading to growth versus cytoskeletal reorganization in T cells, (3) to identify protein serine-threonine kinases located downstream of Vav, and (4) to analyze the ability of wild-type and mutated Vav to reconstitute T-cell development and TCR-mediated activation in Vav-deficient mice.